Endothelial cell activation and/or injury is thought to be an initiating event in the development of atherosclerosis. This disease and its attendant complications such as coronary artery thrombosis represent the number one cause of mortality in this country. This renewal application of the Program Project, consisting of six individual scientific components and a core facility, sets specific objectives to define the mechanisms involved in the pathogenesis of thrombo-atherosclerosis. Through active collaborations, we will test the hypothesis that soluble mediators (eicosanoids, growth factors, cytokines) some of which are thromboregulators regulate vascular cell reactivity, cell adhesion, and phenotype. Specific aims of this continuation application will focus on interactions between hematological and vascular cells in an attempt to elucidate the role of these interactions on the functional metabolic properties of the vessel wall. Particular emphasis will be placed on the role of fluid-phase and cell-associated thromboregulators (PGI/2, NO; ecto-ADPase) on vascular cell reactivity; cellular processes related to naturally-occurring "negative" thromboregulators; the engagement of specific monocyte attachment receptors which transduce intracellular signals that alter the phenotype of vascular cells; and, coordinate induction of specific intracellular pathways which mediate arterial cell migration. The overall program project is designed to utilize the complimentary and non-overlapping research expertise of our vascular biology group to promote synergistic interactions. Our on-going collaborative efforts, where our PPG Vascular Biology group- (six principal investigators) has published 102 peer-reviewed, basic research papers together during the past 4 years, coupled with our major scientific discoveries, underscores the success of this program at Cornell. As a testament to our achievements, Cornell Medical School has recently developed a new Center of Vascular Biology headed by Dr. David Hajjar. These institutional funds (>$1.0 million) are ear-marked for modern capital improvements such as alterations/renovations and new equipment as well as faculty recruitment and development.